This program is aimed at the synthesis and antitumor evaluation of a series of 6-alkenyluracils, and is intended to amplify and extend the earlier findings that 6-vinyluracil and 6-(2-bromoethylacrylyl)-uracil are active in vivo against a number of experimental tumors in mice. It is highly likely that these lead compounds function as alkylating agents, although there seems to be no clear-cut relationship between the rate at which the derivatives prepared to date react with cysteine and their in vitro growth inhibitory activity. It is now proposed to examine compounds with a much wider range of substituent groups, with the overall goal of developing compounds with enhanced levels of antitumor activity. Specifically, two classes of compounds are proposed. Class A is comprised of the free pyrimidine bases; pyrimidine nucleosides bearing unsaturated groups at C-6, such as 6-vinyluridine; and compounds where the double bond forms part of another ring. Class B consists of pyrimidine cyclonucleosides in which an alkene moiety comprises the bridging system. As far as is possible, the selection of compounds for synthesis will be guided by the results of biological evaluation. It is suggested that the nucleoside targets might have a different spectrum of activity relative to the free bases by virtue of differences in their uptake and distribution. The target compounds will be evaluated for their ability to inhibit the growth of mouse and human tumor cells in vitro. Several types of assays will be used, including growth inhibition of mouse L1210 and P388 leukemias, and human HL-60 leukemia cell in suspension culture; a clonogenic assay using HT-29 human colon carcinoma cells; and by a colorimetric assay (MTT) using a number of human lung carcinoma cell lines. The in vitro work will be done in-house under the supervision of Dr. E. L. Schwartz. Compounds with significant activity in the cell culture screens will be examined for in vivo activity in mice bearing leukemias or solid tumors. The in vivo work will be done at Memorial Sloan-Kettering Cancer Center. The ability of selected nucleosides of class A to act as inhibitors or substrates of nucleoside phosphorylases will be determined by Dr. M. el Kouni of Brown University, RI. in nucleosides have been shown recently to bind to uridine phosphorylase. The nucleosides of class A, which are expected to adopt the syn conformation, might therefore be inhibitors if they alkylate a nucleophilic site on the enzyme.